Oct., 1948
3505
STERICEFFECTOF METHYLENE GROUPS
transformed to pseudodiosgenin diacetate. 3. Pseudokryptogenin and its diacetate have been reduced catalytically to pseudodiosgenin and its diacetate, respectively.
6. Three practical methods for the transformation of kryptogenin into steroidal hormone intermediates have been described. MEXICO,D. F.
RECEIVED APRIL 15, 1948
[CONTRIBUTION FROM T H E SCHOOL O F C H E X I S T R Y OF T H E UNIVERSITY O F hfINNESOTA]
Steric Effect of Methylene Groups. IV BY RICHARD T. ARNOLD AND JOHNRICHTER‘ By making use of a large variety of physical and chemical methods,2 it has been clearly demonstrated that resonance in aromatic nitro compounds is hindered by ortho substituents R which inhibit coplanarity of the benzenoid ring and the electron-donor (i. e., (CH&N-) or electron-acceptor (i. e., -NOZ) groups. CHa @ CHa
e
\s/
IV
e
and examined in the ultraviolet region. Table I includes a summary of the pertinent absorption maxima and intensities. TABLE I’ Compound
$-Nitro-N,N-dimethylaniline (I, R = H) is essentially a flat molecule due to the contribution of the quinoidal structure to the resonance. As the group R increases in size, there is an increasing repulsion between R and the amino3 and nitro4 groups. Remington3 has shown that the marked ultraviolet absorption (near 380 mp) of certain nitrobenzene derivatives is associated with the quinoidal limiting structure (I). The intensity of this band is steadily reduced as the group R increases in volume. We have made use of this fact in a determination of the relative steric influence of methylene groups in five- and six-membered rings. Compounds 11-V (represented above in their quinoidal limiting structures) have been prepared
co I
/I
o,Q.o
I1
0
(1) This manuscript was written from the Ph.D. thesis of John Richter. Present address: Merck & Company, Rahway, New Jersey. (2) G . W. Wheland, “The Theory of Resonance,” John Wiley and Sons, Inc., New York, N. Y., 1944, p. 136. (a) Remington, THISJOURNAL, 61, 1838 (1945). (4) Brown and Reagan, ibid., e@, 1032 (1947).
I1
4-Amino-7-nitrohydrindene (p-Xitroaniline)
Max. (in mp)
376 (374)
(Molar)
13,900 (15,700)
I11
4-N,N-Dimethylamino-7-nitrohydrindene 387 12,600 (N,N-Dimethyl-p-nitroaniline) (386) (18,290) IV 5-Amino-S-nitro-l,2,3,4-tetrahydronaphthalene 383 11,400 V 5-N,N-Dimethylamino-8-nitro1,2,3,4-tetrahydronaphthalene 364 5,900 a Measurements were made in 95 per cent. ethanol using a Beckman spectrophotometer,
The free amino groups in I1 and IV are not appreciably affected by the ortho substituent^.^ Presumably the difference between I1 and IV can be attributed largely to a steric repulsion between the nitro and methylene groups. When p-nitroaniline is converted into p-nitroN,N-dimethylaniline a considerable increase is observed in the absorption band near 380 mp. This is, perhaps, largely due to the electron repelling effects of the methyl groups which increase the basicity and facilitate electron release toward the nitro group as indicated in I. This effect is more than counterbalanced, however, when ortho substituents are present, and increases with the size of the substituent due to steric inhibition of the resonance. Differences in the extinction coeflicients of I1 and IV and the changes brought about when these two compounds are methylated to give I11 and V strongly support, we believe, the view that rnethylene groups in hydrindene provide a smaller steric
influence than those in the corresponding sixmembered ring of tetralin. The nitroamines examined above were prepared by nitration of the appropriate acetanilide followed by hydrolysis and methylation. Structure proof consisted of converting the para derivatives to the known para-quinones. 0
v1 0
0
Nitration of 4-Acetamidohydriidene .-To a d lstirred. solution of 4-acetamidohydrindene (23 g.) it1 sulfuric acid (100 ml. cooled to -5"), a cold mixture of nitric acid (8.5 ml.) and sulfuric acid (10 ml.) was added slowly enough so that the solution temperature did not exceed 0". After pouring onto ice (450 g.) the solution was boiled for tw? hours to hydrolyze the acetylamines After cooling to 0 , concentrated sulfuric acid (100 ml.) was added cautiously and the whole was left a t 0" overnight. The precipitated sulfate (Fraction 1) was collected on a filter. To the filtrate was added water (900 ml.) and orange needles (4.8 9.) separated a t 0". This was designated Fraction 2. Neutralization of the Eltrate with ammonium hydroxide gave a brown precipitate. This on sublimation at 0.01 mm. and recrystallization from benzene gave 4-amino-7-nitrohydrindene; wt. 6.8 g.; m. p . 140-141 '. $nul. Calcd. for CQHlaNz02: C, 60.65; H, 5.65. Found: C , 60.40; H, 5.76. Fraction 1 was triturated with hot benzene (250 ml.) and Eltered. Treatment of the residue with ammonium hydroxide gave a mixture of amines. Trituration with hot cyclohexane gave a residue consisting of 4-arnino-7nitrohydrindene (1.4 g.) . From the solution 4-amino6-nitrohydrindene (1.9 g.) crystallized; m. p. 109-110°. Anal. Calcd. for CoHloNzOz: C, 60.65; H, 5.65. Found: C, 60.88; H, 5.78. Fraction 2 was recrystallized from cyclohexane and then from alcoohol to give 4-aminod-nitrohydrindene; m. p. 106-107 ; wt. 3.8 g. Anal. Calcd. for CsHloN202: C, 60.65; H, 5.65. Found: C, 60.90; H, 5.79. 4-Acetamido-5-nitrohydrindene.-A mixture of 4amino-5-nitrohydrindene (0.5 9.) and acetic anhydride (6 ml.) was refluxed for ninety minutes and poured into ice water. After neutralizing with ammonium hydroxide, the Froduct was recrystallized from alcohol; m. p. 146147 Anal. Calcd. for CIIHIZN~OS:Cy 59.98; H, 5.46. Found: C, 59.88; H, 5.60. 4-Acetamidod-nitrohydrindene.--The m-nitroamine was acetylated as above; m. p. 189-190'. Anal. Calcd. for CIIHIZNBOI: C, 59.98; H, 5.46. Found: C, 59.79; H, 5.54. 4-Acetamidod-nitrohydrindene.--Prepared as in the case of the other isomers, this compound melted at 172173'. Anal. Calcd. for C I J % ~ N ~ O C, ~ : 59.98; H, 5.46. Found: C, 60.25; H, 5.74. Structure Proof .-(a) 4-Amino-7-nitrohydrindene (0.5 g.) was reduced with hydrogen using platinum in acetic acid (30 ml.). After removing the catalyst a solution containing concentrated sulfuric acid (4 ml.) , potassium dichromate (4.0 g.) and water (50 ml.) was added quickly to the filtrate. From the steam distillate there was obtained 4,7-hydrindenequinone; m. p. 39-40O.6 (b) From 5-amino-8-nitro-l,2,3,4-tetrahydronaphthalene there was formed (using the above procedure) 1,2,3,4tetrahydro-5,8-naphthoquinone; m. p. 55-56 '.a (c) A solution of 4-amino-5-nitrohydrindene(0.5 g.) in absolute ethanol (30 ml.) was reduced with hydrogen (at 10 pounds pressure) in the presence of platinum. The catalyst was removed by filtration and concentrated hydrochloric acid (10 ml.) was added to precipitate the diamine hydrochloride. A mixture of the diamine hydrochloride (0.57 g.), 9,lO-phenanthraquinone (0.55 g.) and acetic acid (30 ml.) was heated under reflux for tw: hours. The precipitated phenazine melted at 245-246 Anal. Calcd. for CBHIBNZ: C, 86.26; H, 5.04. Found: C, 86.18; H, 5.36. This isolation of dibenza[a,c]cyclopenta[jlphenazine proves the relative position of nitro and amino groups as that of ortho.
.
VI11 0
II
Q 0
- co I
Acetamido groups when o-disubstituted resist hydroly~is,~ and thus IX was readily separated from VI11 by partial hydrolysis. As suspected from the above stereo considerations, compound VI is cleaved rapidly enough in acid media so that its separation from VI1 proved quite difficult. The authors are grateful to Dr. Donald Wheeler and Mr. David Terry of the General Mills Research Laboratory for the separation of 4- and 5nitrohydrindenes by means of a Podbielniak column. Experimental 4-Nitrohydrindene.-A mixture of 4- and &nitrohydrindene (399 9 . ) was separated by distillation through a Podbielniak column. About one-third of the material (129 g.) distilled at 105-107' (6 mm.) and Crystallized in the receiver. Recrystallization from alcohol gave 117 g. (17% based on hydriidene used); m. p. 44-45". Reduction with hydrogen and Raney nickel followed by acetylation gave 4acetamidohydrindene in a yield of 82oJoO. (S) Varkade and Witjena. R8c. &or. chim.. 69, 202 (lQ48).
.
(6) Arnold and Zaugg. TEIS J O W P N A L ,63, 1317 (1911),
NOTES
Oct., 1948 4-N,N-Dimethylaminos7-nitrohydrindene.-A mixture containing 4-amino-7-nitrohydrindeae (4 9 . ), sodium hydroxide (4 g.), methyl iodide (17 9.) and methanol (20 ml.) was heated at 140-150" for six hours. The solution was extracted with benzene after having been made alkaline and the benzene was removed by steam distillation. The residue was refluxed with acetic anhydride (30 ml.) for three hours and decomposed with water. Extraction with benzene followed by extraction of the benzene layer with hydrochloric acid (6 N ) and then neutralization gave 4-N,N-dimethylamino-7-nitrohydrindene. Recrystallizationo from alcohol gave 2.9 g. of pure product; m. p. 81-82 Anal. Calcd. for C1IH1dN202: C, 64.06; H, 6.85. Found: C,64.01; H, 7.00. 5-Amino-8-nitro-l,2,3,4-tetrahpdronaphthalene .-5Acetamido-1,2,3,4-tetrahydronaphthalene (18 9 . ) dissolved in sulfuric acid (100 ml.) and nitrated at 0" with nitric acid (6.3 ml.) dissolved in sulfuric acid (30 ml.). The residue obtained after decomposition with ice (800 g.) was taken up in hot alcohol (200 ml.). To this was added hydrochloric acid (80 ml., 6 N ) and the whole was heated under reflux for thirty minutes. One-half of the alcohol was removed by distillation, water (300 ml.) was added and the solution was neutralized with ammonium hydroxide. The solid which formed was
.
3507
dried, dissolved in nitrobenzene (250 ml.) and treated with dry hydrogen chloride for fifteen minutes at 0". A solid (hydrochloride) weighing 14.1 g. was formed. Neutralization by alkali followed by recrystallization from alcohol gave 5-amino-S-nitro-1,2,3,4-tetrahydronaphthalene; wt. 10.2 g.; m. p. 114.5-116O.7 5 -N,N -Dimethylamino -8-nitro-1,2,3,4-tetrahydronaphthalene.-Following the procedure for methylation as described above for the corresponding hydrindene derivative, there was obtained from the amino compound (49.) a 4501yield of the anticipated methylated product; m. p. 61-62 Anal. Calcd. for C12HlsNeOi: C, 65.45; H, 7.32; N, 12.7. Found: C,65.76; H, 7.35; N,12.7.
.
Summary 1. A number of nitroamines in the hydrindene and tetralin series have been prepared. 2. The ultraviolet spectra of these compounds have been used to support the view that methylene groups in five-membered rings offer less steric hindrance than those in six-membered rings. (7) Schiwter, Ann., 426, 60 (1922).
MINNEAPOLIS, MINNESOTA
RECEIVED APRIL30, 1948
NOTES The Homogeneity of the Phenylosazone Prepared from D-Fructose BY W. W. BINKLEY~ AND M. L. WOLFROM
Wolfrom, Thompson and Evans2have reported an instance of phenylosazone formation, in l-desoxy-D-psicose, in which the carbonyl carbon aud the secondary hydroxyl of carbon three were concerned. It was considered of interest to investigate the phenylosazone formation from the ketose D-fructose to determine if the phenylosazone produced might be a mixture of the 1,2 and 2,3 derivatives3 To this end the phenylosazone produced from D-fructose was converted to the phenylosotriazole. The phenylosotriazole obtained was found to be identical with that obtained from D-glucose and which Hann and Hudson4had found to be homogeneous and to produce on periodate oxidation 2-phenyl-4-formyl-osotriazole with the concomitant formation of 1 mole of formaldehyde and 2 moles of formic acid. These oxidation results were confirmed by us on our product and we report further that the oxidation with lead tetraacetate, a homogeneous reaction (the periodate oxidations are heterogeneous), (1) Sugar Research Foundation Associate of The Ohio State University Research Foundation (Project 190). (2) M. L. Wolfrom, A. Thompson and E. F. Evans,THISJOWENAL, 67, 1793 (1946). (3) See E. G. V. Percival, Advances in Carbohydrate Chem., 8, 44 (1948). (4) R.M.Rann and C. S. Hudson, h m Joomwrr. 66, 736 (1944).
yielded the same over-all result. Any 2,3-osazone present would have yielded a phenylosotriazole that would have consumed 2 moles of oxidant with the concomitant formation of 1 mole of formaldehyde, 1mole of formic acid and 2-phenyl-4-formyl5-hydroxymethyl-osotriazole.
s
3
!
1
1
!
100
250
400
Time, min. Fig. 1.-Lead tetraacetate oxidation of phenylosotriazole from D-fructose in 97.5% acetic acid at 25'. Points shown corrected for reagent blanks.
Thus it has been determined that in the normal procedures for preparing phenylosarones and
